Effect of exercise training on left ventricular remodeling in diabetic patients with diastolic dysfunction: rationale and design

This study will examine the effects of combined aerobic and resistance training on left ventricular remodeling in diabetic patients with diastolic dysfunction. This is the first randomized controlled trial to look for effects of combined strength training and aerobic exercise on myocardial function as well as other clinical, functional, or psychological parameters in diabetic patients with isolated diastolic dysfunction, and will provide important insights into the potential management strategies for heart failure with preserved ejection fraction.

Nurse-led titration of angiotensin converting enzyme inhibitors, beta-adrenergic blocking agents and angiotensin receptor blockers for patients with left ventricular systolic dysfunction

This is the protocol for a review and there is no abstract. The objectives are as follows:

To assess the effects of nurse-led titration of ACEIs, beta-adrenergic blocking agents and ARBs in patients with left ventricular systolic dysfunction in terms of safety and patient outcomes.

Telomere dynamics during aging in polygenic left ventricular hypertrophy.

Short telomeres are associated with increased risk of cardiovascular disease. Here we studied cardiomyocyte telomere length at key ages during the ontogeny of cardiac hypertrophy and failure in the hypertrophic heart rat (HHR), and compared these with the normal heart rat (NHR) control strain. Key ages corresponded with the pathophysiological sequence beginning with fewer cardiomyocytes (2-days), leading to left ventricular hypertrophy (LVH) (13-weeks) and subsequently progression to heart failure (38-weeks). We measured telomere length, tissue activity of telomerase, mRNA levels of telomerase reverse transcriptase (Tert) and telomerase RNA component (Terc), and expression of the telomeric regulator microRNA miR-34a. Cardiac telomere length was longer in the HHR compared to the control strain at 2-days and 38-weeks, but shorter at 13-weeks. Neonatal HHR had higher cardiac telomerase activity and expression of Tert and miR-34a. Telomerase activity was not different at 13- or 38-weeks. Tert mRNA and Terc RNA were over-expressed at 38-weeks, while miR-34a was over-expressed at 13-weeks but down-regulated at 38-weeks. Circulating leukocytes were strongly correlated with cardiac telomere length in the HHR only. The longer neonatal telomeres in HHR are likely to reflect fewer foetal and early postnatal cardiomyocyte cell divisions and explain the reduced total cardiomyocyte complement that predisposes to later hypertrophy and failure. Although shorter telomeres were a feature of cardiac hypertrophy at 13-weeks, they were not present at the progression to heart failure at 38-weeks.

Elevated intracardiac angiotensin II leads to cardiac hypertrophy and mechanical dysfunction in normotensive mice

Introduction
Angiotensin II (Ang II) is known to induce cardiac growth and modulate myocardial contractility. It has been reported that elevated levels of endogenous Ang II contribute to the development of cardiac hypertrophy in hypertensives. However, the long-term functional effects of cardiac exposure to Ang II in normotensives is unclear.

A recently developed transgenic mouse (TG1306/1R), in which cardiac-specific overproduction of Ang II produces primary hypertrophy, provides a new experimental model for investigation of this phenotype. The aim of the present study was to use this model to investigate whether there is a functional deficit in primary hypertrophy that may predispose to cardiac failure and sudden death. We hypothesised that primary cardiac hypertrophy is associated with mechanical dysfunction in the basal state.

Methods
Normotensive heterozygous TG1306/1R mice harbouring multiple copies of a cardiac-specific rat angiotensinogen gene were studied at age 30—40 weeks and compared with age-matched wild-type littermates. Left ventricular function was measured ex vivo in bicarbonate buffer-perfused, Langendorffmounted hearts ( at a perfusion pressure of 80 mmHg, 37°C) using a fluid-filled PVC balloon interfaced to a pressure transducer and digital data acquisition system.

Results
There was no difference in the mean (±SEM) intrinsic heart rate of TG1306/1R and wild-type control mice (357.4±11.8 vs. 367.5±20.9 bpm, n=9 & 7). Under standardised end-diastolic pressure conditions, TG1306/1R hearts exhibited a significant reduction in peak developed pressure (132.2±9.4 vs. 161.5±3.1 mmHg, n=9 & 7, p<0.05) and maximum rate of pressure development (3566.7±323.7 vs. 4486.3±109.4 mmHg, n=9 & 7, p<0.05). TG1306/1R mice show a significant correlation between incidence of arrhythmia and increasing heart size (Spearman's correlation coefficient 0.61).

Conclusion
These data demonstrate that chronic in vivo exposure to elevated levels of intra-cardiac Ang II is associated with significant contractile abnormalities evident in the ex vivo intact heart. Our findings suggest that endogenous overproduction of cardiac Ang II, independent of changes in blood pressure, is sufficient to induce ventricular remodelling that culminates in impaired cardiac function which may precede failure.

Exercise and Sports Science Australia position statement on exercise training and chronic heart failure

Chronic heart failure (CHF) is a complex syndrome characterised by progressive decline in left ventricular function, low exercise tolerance and raised mortality and morbidity. Regular exercise participation has been shown to be a safe and effective treatment modality in the majority of CHF patients, partially reversing some of the maladaptations evident in myocardial and skeletal muscle function, and resulting in improvements in physical fitness and quality of life, and perhaps reduced mortality. The volume and intensity of exercise that is recommended depends on the syndrome severity, however in most patients it should consist of a combination of low-to-moderate intensity aerobic (endurance) exercise on most days of the week and individually prescribed low-to-moderate intensity resistance (strength) training at least twice per week. Additionally, all patients should be closely monitored prior to and during exercise for contraindications by an appropriately trained health professional. The purpose of this statement is to inform and guide exercise practitioners and health professionals in the safe and effective prescription and supervision of exercise for patients with CHF.

Cardiac structure and function in young endurance athletes and nonathletes

The purpose of this study was to examine, in male adolescents, the effects of long-term endurance training on cardiac structure and function, by adopting a cross-sectional comparison with a nonathletic control group. A total of 13 endurance-trained (EX) and seven untrained (CON) male adolescents (mean ± SE, age = 15.3 ± 0.3 and 15.2 ± 0.28 yrs, respectively) underwent echocardiography at rest to determine left ventricular enddiastolic dimension (LVD_d), left ventricular end-systolic dimension (LVD_s), left ventricular posterior wall thickness (LVPW), stroke volume (SV), and cardiac output (CO). On separate days, incremental exercise tests were conducted on a cycle ergometer to measure peak oxygen uptake (VO_2max) and anaerobic power. VO_2max was greater in the endurance group (54.4 ± 1.8 mL min^–1 kg^–1) than in the control group (45.8 ± 1.6 mL min^–1 kg^–1; p < 0.05). Mean exercise time was longer in EX (12.9 ± 0.7 min) than CON (10.4 ± 0.8 min; p < 0.05). No significant differences were noted between the two groups in resting heart rate, maximal heart rate, LVD_d, LVD_s, LVPW, SV, SV indexed, CO, and CO indexed, or in the anaerobic strength. These data provide evidence that endurance-trained adolescent males develop superior exercise performance before the cardiac remodeling that is evident in trained adult athletes.

Analysis of cardioprotective effects using purified Saliva miltiorrhiza extract on isolated rat hearts

The purpose of the current study is to evaluate the cardioprotective effects of purified Salvia miltiorrhiza extract (PSME) on myocardial ischemia/reperfusion injury in isolated rat hearts. Hearts were excised and perfused at constant flow (7 – 9 ml · min⁻¹) via the aorta. Non-recirculating perfusion with Krebs-Henseleit (KH) solution was maintained at 37°C and continuously gassed with 95% O₂ and 5% CO₂. KH solution with or without PSME (100 mg per liter solution) was used after 30-min zero-flow ischemia for the PSME and control group, respectively. Left ventricular (LV) developed pressure; its derivatives, diastolic pressure, and so on were continuously recorded via a pressure transducer attached to a polyvinylchloride balloon that was placed in the left ventricle through an incision in the left atrium. PSME treated hearts showed significant postischemic contractile function recovery (developed pressure recovered to 44.2 ± 4.9% versus 17.1 ± 5.7%, P<0.05; maximum contraction recovered to 57.2 ± 5.9% versus 15.1 ± 6.3%, P<0.001; maximum relaxation restored to 69.3 ± 7.3% versus 15.4 ± 6.3%, P<0.001 in the PSME and control group, respectively). Significant elevation in end-diastolic pressure, which indicated LV stiffening in PSME hearts might have resulted from the excess high dose of PSME used. Further study will be conducted on the potential therapeutic value with lower dose of PSME on prevention of ischemic heart disease.

Isoflavones from red clover improve systemic arterial compliance but not plasma lipids in menopausal women

The possibility that the heightened cardiovascular risk associated with the menopause can be reduced by increasing dietary isoflavone intake was tested in 17 women by measuring arterial compliance, an index of the elasticity of large arteries such as the thoracic aorta. Compliance diminishes with age and menopause. An initial 3- to 4-week run-in period and a 5-week placebo period were followed by two 5-week periods of active treatment with 40 mg and then 80 mg isoflavones derived from red clover containing genistein, daidzein, biochanin, and formononetin in 14 and 13 women, respectively, with 3 others serving as placebo controls throughout. Arterial compliance, measured by ultrasound as a pressure (carotid artery) and volume (outflow into aorta) relationship, was determined after each period; plasma lipids were measured twice during each period. Urinary output of isoflavones was also determined. Arterial compliance rose by 23% relative to that during the placebo period with the 80-mg isoflavone dose and slightly less with the 40-mg dose (mean6SEM: placebo, 19.761.5; 40 mg, 23.760.7; 80 mg, 24.46 1.4). In the three women receiving continuous placebo, compliance was 16 6 2.2, similar to that during the run-in period for the remaining subjects (17 6 2.1). ANOVA showed a significant (P 5 , 0.001) difference between treatments; by Bonferroni multiple comparisons and by paired t test, differences were significant between placebo and 40- and 80-mg isoflavone doses (by paired t test: P50.039 for placebo vs. 40 mg; P 5 0.018 for placebo vs. 80 mg). Plasma lipids were not significantly affected. An important cardiovascular risk factor, arterial compliance, which diminishes with menopause, was significantly improved with red clover isoflavones. As diminished compliance leads to systolic hypertension and may increase left ventricular work, the findings indicate a potential new therapeutic approach for improved cardiovascular function after menopause.

Reperfusion-induced myocardial dysfunction is prevented by endogenous annexin-A1 and its N-terminal-derived peptide Ac-ANX-A12-26

BACKGROUND AND PURPOSE : Annexin-A1 (ANX-A1) is an endogenous, glucocorticoid-regulated anti-inflammatory protein. The N-terminal-derived peptide Ac-ANX-A12–26 preserves cardiomyocyte viability, but the impact of ANX-A1-peptides on cardiac contractility is unknown. We now test the hypothesis that ANX-A1 preserves post-ischaemic recovery of left ventricular (LV) function.

EXPERIMENTAL APPROACH : Ac-ANX-A12–26 was administered on reperfusion, to adult rat cardiomyocytes as well as hearts isolated from rats, wild-type mice and mice deficient in endogenous ANX-A1 (ANX-A1–/–). Myocardial viability and recovery of LV function were determined.

KEY RESULTS: Ischaemia–reperfusion markedly impaired both cardiomyocyte viability and recovery of LV function by 60%. Treatment with exogenous Ac-ANX-A12–26 at the onset of reperfusion prevented cardiomyocyte injury and significantly improved recovery of LV function, in both intact rat and wild-type mouse hearts. Ac-ANX-A12–26 cardioprotection was abolished by either formyl peptide receptor (FPR)-nonselective or FPR1-selective antagonists, Boc2 and cyclosporin H, but was relatively insensitive to the FPR2-selective antagonist QuinC7. ANX-A1-induced cardioprotection was associated with increased phosphorylation of the cell survival kinase Akt. ANX-A1−/− exaggerated impairment of post-ischaemic recovery of LV function, in addition to selective LV FPR1 down-regulation.

CONCLUSIONS AND IMPLICATIONS : These data represent the first evidence that ANX-A1 affects myocardial function. Our findings suggest ANX-A1 is an endogenous regulator of post-ischaemic recovery of LV function. Furthermore, the ANX-A1-derived peptide Ac-ANX-A12–26 on reperfusion rescues LV function, probably via activation of FPR1. ANX-A1-based therapies may thus represent a novel clinical approach for the prevention and treatment of myocardial reperfusion injury.

Cardiac adaptation to endurance exercise in rats

Endurance exercise is widely assumed to improve cardiac function in humans. This project has determined cardiac function following endurance exercise for 6 (n = 30) or 12 (n = 25) weeks in male Wistar rats (8 weeks old). The exercise protocol was 30 min/day at 0.8 km/h for 5 days/week with an endurance test on the 6th day by running at 1.2 km/h until exhaustion. Exercise endurance increased by 318% after 6 weeks and 609% after 12 weeks. Heart weight/kg body weight increased by 10.2% after 6 weeks and 24.1% after 12 weeks. Echocardiography after 12 weeks showed increases in left ventricular internal diameter in diastole (6.39 ± 0.32 to 7.90 ± 0.17 mm), systolic volume (49 ± 7 to 83 ± 11 μl) and cardiac output (75 ± 3 to 107 ± 8 ml/min) but not left wall thickness in diastole (1.74 ± 0.07 to 1.80 ± 0.06 mm). Isolated Langendorff hearts from trained rats displayed decreased left ventricular myocardial stiffness (22 ± 1.1 to 19.1 ± 0.3) and reduced purine efflux during pacing-induced workload increases. 31P-NMR spectroscopy in isolated hearts from trained rats showed decreased PCr and PCr/ATP ratios with increased creatine, AMP and ADP concentrations. Thus, this endurance exercise protocol resulted in physiological hypertrophy while maintaining or improving cardiac function.

Cardiovascular alterations and management

This chapter reviews the support of cardiovascular function in the face of
many compromises to the system. It focuses on two of the most prevalent and fatal diseases affecting the heart: coronary heart disease and heart failure. These diseases are also a common comorbidity in elderly patients admitted to critical care units. The first section on coronary heart disease reviews the pathophysiological concepts of myocardial ischaemia and associated complications, with detailed consideration of the clinical implications, assessment and associated management. Heart failure is discussed in terms of the body’s compensatory mechanisms and the clinical sequelae and associated clinical features of heart failure. Nursing and medical management is outlined including the management of acute exacerbations of heart failure. Finally, other cardiovascular disorders commonly managed in critical care units are reviewed, ranging from other forms of heart failure to hypertensive emergencies and aortic aneurysms. The case study presented at the end of the chapter highlights the key aspects of the management of coronary heart disease and heart failure in patients admitted to critical care units.

Analyzing systolic-diastolic interval interaction characteristics in diabetic cardiac autonomic neuropathy progression

Cardiac autonomic neuropathy (CAN), one of the major complications in diabetes, if detected at the subclinical stage allows for effective treatment and avoiding further complication including cardiovascular pathology. Surface ECG (Electrocardiogram)-based diagnosis of CAN is useful to overcome the limitation of existing cardiovascular autonomic reflex tests traditionally used for CAN identification in clinical settings. The aim of this paper is to analyze the changes in the mechanical function of the ventricles in terms of systolic-diastolic interval interaction (SDI) from a surface ECG to assess the severity of CAN progression [no CAN, early CAN (ECAN) or subclinical CAN, and definite CAN (DCAN) or clinical CAN]. ECG signals recorded in supine resting condition from 72 diabetic subjects without CAN (CAN-) and 70 diabetic subjects with CAN were analyzed in this paper. The severity of CAN was determined by Ewing's Cardiovascular autonomic reflex tests. Fifty-five subjects of the CAN group had ECAN and 15 subjects had DCAN. In this paper, we propose an improved version of the SDI parameter (i.e., TQ/RR interval ratio) measured from the electrical diastolic interval (i.e., TQ interval) and the heart rate interval (i.e., RR interval). The performance of the proposed SDI measure was compared with the performance of the existing SDI measure (i.e., QT/TQ interval ratio). The proposed SDI parameter showed significant differences among three groups (no CAN, ECAN, and DCAN). In addition, the proposed SDI parameter was found to be more sensitive in detecting CAN progression than other ECG interval-based features traditionally used for CAN diagnosis. The modified SDI parameter might be used as an alternative measure for the Ewing autonomic reflex tests to identify CAN progression for those subjects who are unable to perform the traditional tests. These findings could also complement the echocardiographic findings of the left ventricular diastolic dysfunction by providing additional information about alteration in systolic and diastolic intervals in heart failure.